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Kynurenines in the mammalian brain: when physiology meets pathology
Open accessAbstract
The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.
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“Kynurenine and its metabolites, including kynurenic acid and quinolinic acid, have been implicated in mental health (Cervenka et al., 2017;Schwarcz et al., 2012).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Schwarcz et al., 2012
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“Mounting evidence suggests that the GM modulates the tryptophan and kynurenine pathways and is a humoral route through which the GM may influence cognition at the level of the CNS (206–210).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [209]
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“Other metabolites of tryptophan metabolism, kynurenines, have also been implicated in a range of neurobiological functions (392).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [392]
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“TRP is a precursor for 5-HT, and it also metabolized by kynurenine pathway which initiated by the TDO2 (tryptophan 2,3-dioxygenase) [19].”
BackgroundPhysical exercise prevents mice from L-Kynurenine-induced depression-like behavior.
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Kynurenine pathway metabolites: relevant to vitamin B-6 deficiency and beyond
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“3-HK is sequentially transformed into 3-hydroxyanthranilic acid (3-HANA) and quinolinic acid (QUINA), or, alternatively, is transminated by KAT into xanthurenic acid (XA) 19,20 .”
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Effective factors in the pathogenesis of Toxoplasma gondii
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“Tryptophan catabolism products in the rise in brain oxidative stress, cell damage, and apoptosis [386].”
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“Estrogen levels increase dramatically before delivery, reaching 1000 times their base-line values, then drop quickly after delivery with substantial individual di ff erences. branches arise partly from their distinct glutamatergic activity at the NMDAR [93].”
BackgroundThe effect of electroconvulsive therapy (ECT) on serum tryptophan metabolites
Aarsland, T. I. M., Leskauskaite, I., Midttun, Ø., Ulvik, A., Ueland, P. M., Oltedal, L., Erchinger, V. J., Oedegaard, K. J., Haavik, J., & Keßler, U. (2019) · Brain stimulation · doi:10.1016/j.brs.2019.05.018 · Cited by 23
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“In he CNS, approximately 60% of KYN c mes from blood, and the rest is ynthes zed locally from he TRP p ol [34].”
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Tao, Q., Shen, Y., Li, Y., Luo, H., Yuan, M., & Gan, J. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.1045865 · Cited by 26
“Immune activation has also been linked to the pathogenesis of major depressive disorder (47) and schizophrenia (48) in adults.”
BackgroundThe evolution of small molecule enzyme activators
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“Similarly, SZR-104 has been shown to modulate immune systems and inhibit glutamate receptors with effects similar to KYNA [168].”
BackgroundOn the toxicity of kynurenic acid in vivo and in vitro
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Impact of neuroinflammation on brain glutamate and dopamine signalling in schizophrenia: an update
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“In contrast, olanzapine or risperidone did not show to inflammatory mediators (Schwarcz et al. 2012).”
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Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia
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Identification and characterization of the kynurenine pathway in the pond snail Lymnaea stagnalis
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“TheKPhas been investigated since the early twentieth century [8] but its importance was long thought to be linked primarily to the de novo synthesis of nicotinamide and, consequently, nicotinamide adenine dinucleotide, a coenzyme involved in several biological processes such as redox reactions required for mitochondri…”
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“In patients with severe psychiatric disorders, the risk of irregular sleep patterns is two-fold higher compared to healthy controls, and thus, expectedly, the prevalence of sleep disturbances is 80% amongst individuals with schizophrenia (SCZ) and bipolar disorder (BPD) (2, 3).”
BackgroundInfluentialA review of the pharmacological action and mechanism of natural plant polysaccharides in depression
Yang, Y., Li, C.-X., Zhang, R., Shen, Y. H., Xu, X., & Yu, Q. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1348019 · Cited by 30
“Simultaneously, an elevation in KYN, another metabolite of TRP, contributes to the development of depressive symptoms through immune dysregulation and induction of neuroin fl ammation (Schwarcz et al., 2012; Gong et al., 2023).”
BackgroundAtlas, A., Franzen-Röhl, E., Söderlund, J., Jönsson, E. G., Samuelsson, M., Schwieler, L., Sköldenberg, B., & Engberg, G. (2013) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s13256 · Cited by 25
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Metadata
- Authors
- Schwarcz, R., Bruno, J. P., Muchowski, P. J., & Wu, H.-Q.
- Affiliations
- University of Maryland, Baltimore (US)
- The Ohio State University (US)
- University of California, San Francisco (US)
- Corresponding author
- Schwarcz, Robert
- Venue
- Nature Reviews Neuroscience
- Published
- 2012-06-08
- Volume
- 13
- Issue
- 7
- Pages
- 465-477
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC3681811
- OpenAlex
- W2060050678
- Cited by
- 1,530
- References
- 215
- Citations by year
- 2026: 157 · 2025: 137 · 2024: 124 · 2023: 98 · 2022: 118 · 2021: 145 · 2020: 132 · 2019: 95 · 2018: 83 · 2017: 96 · 2016: 98 · 2015: 105 · 2014: 64 · 2013: 63 · 2012: 13
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH083729)
- National Institute of Neurological Disorders and Stroke (R01NS057715)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- kynurenine pathway, tryptophan metabolism, kynurenic acid, 3-hydroxykynurenine, quinolinic acid, neuroactive metabolites, neurodegenerative diseases, depression, schizophrenia, therapeutic targeting
- MeSH terms
- Animals, Brain, Humans, Kynurenine, Nervous System Diseases, Signal Transduction
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